Abstract
Balanced processing of HIV-1 RNA is critical to virus replication and is regulated by host factors. In this report, we demonstrate that overexpression of either Tra2α or Tra2β results in a marked reduction in HIV-1 Gag/ Env expression, an effect associated with changes in HIV-1 RNA accumulation, altered viral splice site usage, and a block to export of HIV-1 genomic RNA. A natural isoform of Tra2β (Tra2ß3), lacking the N-terminal RS domain, also suppressed HIV-1 expression but had different effects on viral RNA processing. The functional differences between the Tra2β isoforms were also observed in the context of another RNA substrate indicating that these factors have distinct functions within the cell. Finally, we demonstrate that Tra2ß depletion results in a selective reduction in HIV-1 Env expression as well as an increase in multiply spliced viral RNA. Together, the findings indicate that Tra2α/β can play important roles in regulating HIV-1 RNA metabolism and expression.
Highlights
Regulation of alternative splicing is thought to play a critical role in the function of a cell
To explore in greater detail how these factors alter HIV-1 RNA processing, we looked for changes in splice site usage by RT—PCR in both the singly and multiply spliced viral RNAs for a listing and description of the spliced products generated by HIV-1)
Studies to date have highlighted a significant role for SR proteins in regulating HIV-1 RNA processing and expression, different members of the SR protein family yielding distinct effects upon either overexpression or depletion [30, 48,49,50,51]
Summary
Regulation of alternative splicing is thought to play a critical role in the function of a cell. Predictions are that >90% of the mRNAs in the human genome undergo alternative splicing (reviewed in [1, 2]). Alternative splicing allows the sequence complexity of the genome to be dramatically increased from the ~25,000 genes currently predicted. This point is true for HIV-1, the integrated provirus generating a single 9 kb transcript that is processed by alternative splicing to generate ~40 mRNAs to produce the proteins essential for new virion formation [3, 4]. One component in the regulation of RNA alternative splicing is represented by the host cell SR proteins. Unlike SR proteins, SRrelated proteins are unable to support constitutive splicing in S100 extracts
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